Effect of the potassium-channel opener nicorandil as an adjunct to cardioplegia on myocardial preservation in isolated rabbit hearts

We studied the effect of nicorandil on the hemodynamic, biochemical, and ultrastructural changes in rabbit hearts (n=50) rendered cardioplegic with a single injection of Bretschneider's HTK solution over 30min or 60min at 37°C or 15°C, followed by reperfusion at 37°C for 60min. Particular attention was focused on the aspects of doseresponse relationship, temperature sensitivity, and ischemic tolerance. Isolated hearts were prepared for modified Langendorff circulation using modified Krebs-Henseleit bicarbonate solution bubbled with a 95% O₂-5% CO₂ gas mixture, to which nicorandil (0, 0.1, 1, and 5 mM) was added. The optimal concentration of nicroandil was 1 mM, which increased the recovery of left ventricular (LV) function, affecting coronary flow and the myocardial cyclic adenosine monophosphate, but not the myocardial concentrations of adenine nucleotide compounds or total calcium. These effects were abolished by the addition of glibenclamide to the HTK, but they were not diminished by a high potassium (K⁺) concentration of 20 mM. The addition of nicorandil 1 mM to the HTK at 15°C did not improve the recovery of LV function. Our result suggested that nicorandil used adjunctly prevents LV functional depression after 30 min, and possibly 60 min of cardioplegia at 37°C, and that this effect is not disturbed by a high K⁺ concentration up to 20 mM. However, nicorandil has temperature sensitivity whereby it loses its efficacy at 15°C.     

The adenosine triphosphate-sensitive potassium channel opener nicorandil protects the ischemic rabbit spinal cord

OBJECTIVE: We investigated the protective effects of an adenosine triphosphate-sensitive potassium channel opener nicorandil in the rabbit model of spinal cord ischemia. METHODS: Rabbits were randomized into 4 groups (each n = 6): the nicorandil group (100 microg/kg intravenous nicorandil 10 minutes before ischemia); the glibenclamide plus nicorandil group (3 mg/kg intravenous glibenclamide, an antagonist of adenosine triphosphate-sensitive potassium channels, 10 minutes before nicorandil administration); the vehicle group (vehicle alone); and the sham operation group (without spinal cord ischemia). Spinal cord ischemia was induced by balloon occlusion of the infrarenal abdominal aorta for 15 minutes at 39 degrees C. Neurologic function was graded into Johnson's score at 8 hours, 1 day, and 2 days. Histopathologic examination was performed at 2 days, and the number of intact motor neuron cells was compared. RESULTS: Johnson scores of the glibenclamide plus nicorandil and vehicle groups were significantly lower than those of the sham operation and nicorandil groups at each time point, and no statistically significant difference was observed between the glibenclamide plus nicorandil and vehicle groups. Histopathologic examination revealed that motor neurons were almost normal in the nicorandil group, whereas about 55% of motor neurons were lost in the vehicle and glibenclamide plus nicorandil groups. CONCLUSIONS: Nicorandil has a protective effect on the ischemic rabbit spinal cord, and the beneficial effect seems mediated through the activation of adenosine triphosphate-sensitive potassium channels.     

钾通道开放剂心脏超极化停搏保护效果的研究

目的 对比观察大量三磷酸腺苷（ＡＴＰ）敏感性钾通道开放剂吡那地尔对常温／低温体外循环（ＣＰＢ）心脏超极化停跳缺血心肌的保护作用。方法 １８只犬随机分３组,每组６只,低温超极化组（ＬＨ）：阻断升主动脉后,心脏灌注４℃含吡那地尔停跳液,ＣＰＢ血温为２６～２８℃,开放前复温至３７℃,全心缺血６０ｍｉｎ,恢复灌注３０ｍｉｎ;常温超极化组（ＷＨ）：ＣＰＢ血温３５～３７℃,心脏灌注３７地７０含吡那地尔（５０μｍｏｌ／Ｌ）停跳液,余同ＬＨ组;对照组（Ｃ）;无吡那地尔的标准Ｓｔ、Ｔｈｏｍａｓ停跳液,余３７℃含昆那地尔（５０ｕｍｏｌ／Ｌ）停跳液,余同ＬＨ组;对照组（Ｃ）：无吡那地尔的标准Ｓｔ．Ｔｈｏｍａｓ停跳液,余同ＬＨ组,对比观察吡那地尔心脏超极化停跳不同时相各项指标的变化。结果 （１）停复跳情况：ＬＨ组、Ｃ组灌注后心脏停跳较     

Inhibitory effects of nicorandil, a K ATP channel opener and a nitric oxide donor, on overactive bladder in animal models

OBJECTIVES

To investigate the effects of nicorandil, an ATP‐sensitive potassium (K_ATP) channel opener with a nitric oxide (NO) donor property, on overactive bladder (OAB) in animal models. Nicorandil is currently used clinically to treat ischaemic heart disease.

MATERIALS AND METHODS

Three animal OAB models were used: (i) C‐fibre mediated bladder overactivity by infusion of a low concentration of acetic acid (AA) into the bladder in female Wistar rats; (ii) bladder outlet obstruction (BOO) created by partial urethral obstruction in female Wistar rats; and (iii) neuronal NO synthase (nNOS) knockout (KO) mice with urinary frequency. The effects of nicorandil and KRN2391, both of which act as K_ATP channel openers and NO donors, on the OAB models were examined.

RESULTS

Cystometry showed that intravesical instillation of nicorandil and KRN2391 successfully inhibited OAB induced by intravesical instillation of AA. In the BOO model compared with untreated BOO rats, both nicorandil (1 and 3 mg/kg, orally) and KRN2391 (1 mg/kg, orally) significantly reduced the voiding frequency. Compared with wild‐type mice, nNOS KO mice had urinary frequency with no change in the total urine volume. Nicorandil (3 mg/kg, orally) and KRN2391 (1 mg/kg, orally) significantly reduced the voiding frequency in nNOS KO mice.

CONCLUSIONS

Our in vivo results show that nicorandil, a K_ATP channel opener with a NO donor property, can suppress OAB from both neurogenic and myogenic causes. Nicorandil appears to be a promising candidate for clinical use in patients with OAB.     

Dose-dependent prophylactic effect of nicorandil, an ATP-sensitive potassium channel opener, on intra-operative myocardial ischaemia in patients undergoing major abdominal surgery

Nicorandil, a nicotinamide nitrate derivative, relaxes vascularsmooth muscle and reduces cardiac muscle contractility by increasingmembrane potassium conductance, probably by activating ATP-sensitivepotassium channels. In this prospective, randomized, double-blind,placebo-controlled clinical study, we examined the dose-dependentprophylactic effect of nicorandil on intra-operative myocardialischaemia in 248 patients who had pre-operative risk factorsfor ischaemic heart disease and were undergoing major abdominalsurgery. Patients in group HD (n=81) received a bolus dose ofnicorandil 0.08 mg kg^–1 and a continuous infusion of 0.08mg kg^–1 h^–1. Patients in group LD (n=87) receivednicorandil 0.04 mg kg^–1 and 0.04 mg kg^–1 h^–1.Patients in the placebo (P) group (n=80) received the same volumesof saline. The patients were monitored with a three-lead clinicalECG monitor with an ST trending device from arrival in the operatingtheatre to the end of anaesthesia. Intra-operative myocardialischaemia occurred significantly less frequently in the HD group(one patient, 1.2%) than in the LD (11 patients, 12.6%) andP groups (21 patients, 26.3%) (P<0.01), and in group LD significantlyless than in group P (P<0.05). Administration of nicorandilhad little effect on the patients’ heart rate or arterialpressure. Three patients in group P and none in either treatmentgroup developed myocardial infarction after surgery. Br J Anaesth 2001; 86: 332–7     

Inhibition of cyclooxygenase-2 improves cardiac function following long-term preservation

BACKGROUND: Cyclooxygenase (COX) is an intracellular enzyme that converts arachidonic acid to prostaglandin endoperoxide (PGG(2)). There are two isoforms of COX, namely constitutive COX-1 and inducible COX-2. It has been reported that COX-2 plays an important role in ischemia-reperfusion injury and that COX-2 mRNA and protein expression were up-regulated during cardiac allograft rejection. FK3311 is a suppressor of COX-2 activation. The purpose of this study was to evaluate the effectiveness of inhibiting COX-2 with FK3311 for the minimization of ischemia-reperfusion injury and for the improvement of donor heart function following transplantation in a canine model. MATERIALS AND METHODS: Adult mongrel dogs were used. After the measurement of hemodynamic parameters [cardiac output (CO), left ventricular pressure (LVP), and the maximum rates of increase and decrease in LVP (+/-LVdp/dt)], coronary vascular beds were washed out with a hypothermic (4 degrees C) University of Wisconsin (UW) solution following cardiac arrest in response to cold (4 degrees C) glucose-insulin-potassium solution. The heart was then excised and preserved in hypothermic (4 degrees C) UW solution for 12 h. FK3311 (3 mg/kg) was administered intravenously to five dogs prior to reperfusion, while vehicle was administered intravenously to a control group (n = 5). After 3 h of orthotopic transplantation using cardiopulmonary bypass, the hemodynamic parameters were compared with preoperative values of the donor animals under the condition of 10 mm Hg right atrial pressure and 5 mug/kg/min dopamine support. RESULTS: The recovery rates of CO and +/-LVdP/dt were significantly (P < 0.05) higher in the FK-treated dogs than in the controls (CO: 93 +/- 6 versus 66% +/- 4%; +LVdp/dt: 125 +/- 8 versus 77 +/- 10%; and -LVdp/dt: 81 +/- 7 versus 52 +/- 6%; for FK-treated versus control dogs, respectively). The recovery rate of LVP was higher in the FK-treated dogs than in the controls (90 +/- 5 versus 72 +/- 5%), but this difference was not statistically significant. Immunohistochemical staining revealed that COX-2 expression was reduced significantly in the myocardium of FK-treated dogs compared with controls. CONCLUSION: Hemodynamic parameters following transplantation were improved significantly in dogs treated with FK3311. Therefore, the inhibition of COX-2 improves transplanted cardiac function following long-term preservation.     

钾通道开放剂诱导超极化停跳对离体心脏的保护作用

目的 探讨ＡＴＰ第三性钾通道开放剂（ＫＣＯｓ）Ｐｉｎｃａｉｄｉｌ（５０μｍｏｌ／Ｌ对Ｌａｎｇｅｎｄｏｒｆｆ灌注兔心模型超极化停跳的保护作用。方法 选用离体免心脏２４个，随机分成３组：对照组（Ｃ组）；低温超极化组（ＬＨ组）；常温超极化组（ＷＨ组）。离体兔心Ｌａｎｇｅｎｄｏｒｆｆ模型灌注充氧的Ｋｒｅｂｓ－Ｈｅｎｓｅｌｅｉｔ（Ｋ－Ｈ）液稳定后，ＬＨ组或ＷＨ组分别灌注含Ｐｉｎａｃｉｄｉｌ的４℃或３７℃的Ｓ     

Effect of the potassium channel opener WAY-133537 on the overactive bladder of spinalized rats

AIMS: To test the efficacy of WAY-133537 for the treatment of overactive bladder (OAB) in a chronic paraplegic rat model. MATERIALS AND METHODS: Forty-eight female Sprague-Dawley rats were used in this study. Six animals served as normal controls (without spinal cord transaction (ST)), while 42 rats underwent ST at the 10th thoracic vertebra. Two weeks after ST, cystometrogram (CMG) was performed in six randomly chosen animals to ensure the development of neurogenic detrusor overactivity. The remaining 36 rats were divided into three equal groups, 12 received the vehicle as "paraplegic controls," 12 received WAY-133537 0.3 mg/kg, and 12 received WAY-133537 3 mg/kg. Each "paraplegic control" and treatment group was further divided into two sub-groups (n = 6), with CMG at 3 and 4 weeks after ST, respectively. RESULTS: Two weeks after ST, all "vehicle control" rats developed detrusor overactivity with a mean frequency of 0.96 and 1.48 contractions/min and amplitude of 22.96 and 31.22 cm H(2)O with 1- and 2-week treatment, respectively. Neurogenic detrusor overactivity disappeared from 50% of rats that received WAY-133537 0.3 mg/kg for 1 week, and frequency decreased to 0.41 contractions/min. After 2 weeks of treatment, detrusor overactivity vanished from 67% of the animals with even further reduction in the frequency of detrusor overactivity (0.22 contractions/min, P < 0.01). In rats that received 3 mg/kg of the drug for 1 week, detrusor overactivity disappeared from only one animal with a non-significant decline in frequency. Fifty percent of rats given WAY-133537 at the dose of 3 mg/kg/day for 2 weeks manifested no detrusor overactivity. CONCLUSIONS: WAY-133537 shows efficacy in increasing bladder capacity and reducing the frequency of spontaneous bladder contractions after ST in rats without decreasing voiding pressure.     

Donor heart preservation with the potassium channel opener pinacidil: comparison with University of Wisconsin and St. Thomas' solution.

BACKGROUND: Hyperpolarized arrest with the potassium channel opener pinacidil has been shown to provide effective myocardial protection during short-term global ischemia. This study tested the hypothesis that pinacidil may provide effective long-term protection for heart transplant preservation. METHODS: Four concentrations of pinacidil (50 microM, 100 microM, 0.5 mM, 1.0 mM) mixed in Krebs-Henseleit solution were compared with University of Wisconsin and St. Thomas' Hospital solutions in a Krebs-Henseleit perfused rabbit Langendorff model (n = 6 for each group). Hearts underwent 4 hours of hypothermic (4 degrees C) storage. Over a wide range of volumes, left ventricular systolic function, diastolic compliance, and coronary flow were measured prior to and following storage. Time to mechanical and electrical arrest, and post-ischemic percent tissue water were also measured. RESULTS: Pinacidil 0.5 mM provided the best preservation of post-ischemic systolic function and coronary flow compared with the other pinacidil concentrations and was statistically equivalent to St. Thomas' solution in terms of post-ischemic systolic, diastolic, and flow properties. However, hearts protected with University of Wisconsin solution had significantly better preservation of systolic function and coronary flow. CONCLUSIONS: This investigation demonstrated that pinacidil in Krebs-Henseleit solution possesses efficacy in long-term donor heart preservation. Pinacidil was equivalent to St. Thomas' solution but inferior to University of Wisconsin solution. Hyperpolarized arrest with potassium channel openers may be a novel strategy to improve donor heart preservation.     

尼可地尔超极化心脏保存液保存兔心的效果

目的 研究钾通道开放剂尼可地尔（nicorandil）在心脏保存中的作用。方法 40个兔心随机分成4组，分别用含尼可地尔的KH液（超级化心脏保存液）、UW液、STH液和KH液保存。采用Langendorff灌注模型和工作心模型，保存前、后测左室发展压、心室内压上升最大速率、心室内压下降最大速率、冠状动脉流量、肌酸激酶及乳酸脱氢酶，记录各组心跳停止和心电活动停止所需时间、心肌含水量、保存后心肌ATP含量。结果 尼可地尔组的各项指标（除心肌含水量外）均优于STH组和KH组，达到了UW液的效果，结论 尼可地尔超级化心脏保存液保存兔心效果较好。     

Effect of long-term preservation on the mechanical properties of cortical bone in goats

Background and purpose?Bones used in mechanical studies are frequently harvested from human cadavers that have been embalmed in a buffered formaldehyde solution. It has been reported that formaldehyde fixation or freezing hardly affects the mechanical properties of bone after a storage period of several weeks. However, human cadaver bones are usually stored for longer periods of time before use. We therefore investigated the effects of long-term embalming or freezing on the mechanical properties of cortical bone.

Methods?After 5 different storage periods (ranging from 0 to 12 months), goat femora and humeri were used to evaluate the effect of embalming and freezing on torsion, and on bending stiffness and strength. The effect on hardness and bone mineral density (BMD) was also evaluated.

Results?Even after 1 year, no statistically significant differences could be found in stiffness, strength, and energy absorption when we compared embalmed or frozen bones to a fresh reference group. In addition, although we found no significant change in BMD, there appears to be a tendency to increasing hardness.

Interpretation?We found that there was no effect on the mechanical properties of bone after storage periods of 1 year. We conclude that embalmed or frozen bones can safely be used for mechanical testing, at least for storage periods of up to one year.     

The experimental study on long-term cardiac preservation: the efficacy of low-flow continuous perfusion with fluorocarbon

We compared the effect of simple immersion and continuous perfusion on long-term cardiac preservation, and evaluated the effectiveness of perfusion with oxygenated fluorocarbon solution. The isolated rabbit hearts were preserved for 24 hours at 4 degrees C using the following five preservation techniques: (1) simple immersion with Collins M solution (Group I), (2) perfusion with oxygenated Collins M solution at a flow rate of 10 ml/hr (Group II), (3) perfusion with the same solution as in Group II at a flow rate of 20 ml/hr (Group III), (4) perfusion with oxygenated Collins M solution containing 10% fluorocarbon at a flow rate of 10 ml/hr (Group IV), (5) perfusion with the same solution as in Group IV at a flow rate of 20 ml/hr (Group V). The hearts of Group I showed a significant decrease of myocardial ATP and an increase of myocardial lactate during preservation compared to the hearts of perfusion groups. Assessment of isovolumic left ventricular function following 24-hour preservation using a support animal showed a significant decrease of Max dp/dt and increase of end-diastolic pressure in the hearts of Group I. Perfusion with fluorocarbon (Group IV and V) significantly increased oxygen consumption compared to Group II and III in association with minimum accumulation of myocardial lactate, indicating that aerobic metabolism during preservation is better maintained in the fluorocarbon-perfused hearts. Moreover, CPK release and myocardial water gain during preservation were significantly less, and left ventricular function following preservation was significantly better in these hearts. Increasing the flow rate from 10 ml/hr to 20 ml/hr resulted in sustained increase in perfusion pressure (1.80 +/- 0.53 to 3.70 +/- 0.34 mmHg) and myocardial water content (79.2 +/- 0.4 to 87.2 +/- 0.3%) during preservation in the hearts of Group III, but it did not further improve left ventricular function despite significant enhancement of myocardial oxygen uptake in both Group III and V. These results suggest that hypothermic low-flow continuous perfusion with oxygenated Collins M solution is superior to simple immersion with the same solution for long-term cardiac preservation, and that the addition of fluorocarbon to the perfusate enhances the efficacy of such a perfusion.     

Effect of donor age on long-term survival following cardiac transplantation

BACKGROUND AND AIM: The current shortage of donor hearts has forced the criteria of organ procurement to be extended, leading to increased use of older donor hearts to bridge the gap between demand and availability. Our objective was to analyze the effect of donor age on outcomes after cardiac transplantation. METHODS: We retrospectively studied 864 patients who underwent cardiac transplantation at New York Presbyterian Hospital - Columbia University between 1992 and 2002. Patients were divided into two groups; donor age <40 years (Group A, n = 600) and donor age > or =40 years (Group B, n = 264). RESULTS: Characteristics including gender, body mass index, and cytomegalovirus (CMV) status were significantly different between the two donor age groups. Race, CMV status, toxoplasmosis status, left ventricular assist device prior to transplant, diabetes mellitus, and retransplantation were similar in both the recipient groups, while age, gender, and BMI were different. Early mortality was lower in Group A, 5%, versus 9.5% in Group B. Multivariate analysis revealed recipient female gender (odd ratio (OR) = 1.71), retransplantation (OR = 1.63), and increased donor age (OR = 1.02) as significant predictors of poor survival in the recipient population. Actuarial survival at 1 year (86.7% vs 81%), 5 years (75% vs 65%), and 10 years (56% vs 42%) was significantly different as well with a log rank p = 0.002. CONCLUSIONS: These findings suggest that increased donor age is an independent predictor of long-term survival. However, the shortage of organs makes it difficult to follow strict guidelines when placing hearts; therefore, decisions need to be made on a relative basis.     

Effect of blood transfusion on long-term survival after cardiac operation

BACKGROUND: Blood transfusions have been linked to increased morbidity and mortality. Bleeding during and after cardiac operations and the hemodilution effects of cardiopulmonary bypass commonly result in blood transfusions. Because we could not find any studies evaluating the effects of transfusion on long-term survival after cardiac operation, we sought to determine these effects. METHODS: We studied 1,915 patients who underwent first-time isolated coronary artery bypass operations between July 6, 1994 and December 31, 1997 at our institution. Patients with transfusions were compared with those who had not been transfused. Long-term survival data were obtained from the United States Social Security Death Index. Groups were compared by Cox proportional hazard models, Kaplan-Meier survival plots, and hazard functions. RESULTS: Six hundred forty-nine of 1,915 study patients (34%) received a transfusion during their hospitalization. Transfused patients were older, smaller, and more likely to be female, and had more comorbidity. Transfused patients also had twice the 5-year mortality (15% vs 7%) of nontransfused patients. After correction for comorbidities and other factors, transfusion was still associated with a 70% increase in mortality (risk ratio = 1.7; 95% confidence interval = 1.4 to 2.0; p = 0.001). By multivariate analysis, transfusion, peripheral vascular disease, chronic obstructive pulmonary disease, New York Heart Association functional class IV, and age were significant predictors of long-term mortality. CONCLUSIONS: We found that blood transfusions during or after coronary artery bypass operations were associated with increased long-term mortality.     

Pharmacological preconditioning with the adenosine triphosphate-sensitive potassium channel opener pinacidil

BACKGROUND: Ischemic preconditioning (IPC) decreases infarct size after global or regional ischemia. Potassium channel openers also precondition but are subject to dose-limiting vasodilation. We compared the mechanical and electrophysiological effects of ischemic and pharmacological preconditioning in an isolated rabbit heart model. METHODS: Rabbit hearts were preconditioned with either 10 micromol/L pinacidil alone (P-), 10 micromol/L pinacidil with 10 micromol/L phenylephrine (P+), or two cycles of global ischemia and reperfusion (IPC) before 1 hour of LAD occlusion. Left ventricular pressure, epicardial monophasic action potential duration (APD) and coronary flow were monitored throughout. Infarct size was determined at the end of reperfusion. RESULTS: Regional ischemia uniformly decreased APD (p<0.05). During reperfusion, APDs were prolonged beyond preischemic values in all preconditioned groups (p<0.05). P- and P+ reduced the incidence of fibrillation. P- significantly increased coronary flow (+15%, p = 0.001), whereas IPC and P+ did not. However, IPC and P- significantly decreased systolic function (p<0.05) but P+ did not. In addition, IPC depressed diastolic function (p<0.05) but P- and P+ did not. Infarct size was reduced by all methods (p<0.05). CONCLUSIONS: Pinacidil presents a safe and effective alternative to IPC for preserving the heart during regional ischemia. Its coronary vasodilatory effects are safely and effectively reversed by the addition of phenylephrine.     

Effect of long-term remote ischemic conditioning on inflammation and cardiac remodeling

Background. Remote ischemic conditioning (RIC) protects against acute ischemia-reperfusion injury and may have beneficial effects in patients with stable cardiovascular disease. We investigated the effect of long-term RIC treatment in patients with chronic ischemic heart failure (CIHF). Methods. Prespecified post-hoc analysis of a prospective, exploratory and outcome-assessor blinded study. Twenty-one patients with compensated CIHF and 21 matched controls without heart failure or ischemic heart disease were treated with RIC once daily for 28?±?4 days. RIC was conducted as 4 cycles of 5?minutes upper arm ischemia followed by 5?minutes of reperfusion. We evaluated circulating markers of inflammation and cardiac remodeling at baseline and following long-term RIC. Results. RIC reduced C-reactive protein from 1.5 (0.6–2.5) to 1.3 (0.6–2.1) mg/l following long-term RIC treatment (p?=?.02) and calprotectin from 477 (95% CI 380 to 600) to 434 (95% CI 354 to 533) ng/ml (p?=?.03) in patients with CIHF, but not in matched controls. Overall, RIC did not affect circulating markers related to adaptive or innate immunology or cardiac remodeling in patients with CIHF. Among patients with CIHF and N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels above the geometric mean of 372?ng/l, long-term RIC treatment reduced soluble ST2 (n?=?9) from 22.0?±?3.7 to 20.3?±?3.9?ng/ml following long-term RIC treatment (p?=?.01). Conclusion. Our findings suggest that long-term RIC treatment has mild anti-inflammatory effects in patients with compensated CIHF and anti-remodeling effects in those with increased NT-proBNP levels. This should be further investigated in a randomized sham-controlled trial.     

The potassium channel opener levcromakalim causes expansive remodelling of experimental vein grafts

BACKGROUND: Maintenance of luminal area is essential for the optimal performance of venous bypass grafts. However, injury and response to the arterial circulation evoke vascular remodelling that favors intimal hyperplasia, with luminal encroachment and inward remodelling. Potassium channel-opening drugs reduce tissue workload and peripheral vascular resistance and through these mechanisms could favor outward or expansive remodelling of vein grafts. We tested the hypothesis that levcromakalim, a potassium channel opener, would enhance expansive remodelling in vein grafts. METHODS: A randomized, double-blind, placebo-controlled trial was conducted in 33 rats with vena cava-to-aorta bypass grafts. Drugs were administered via osmotic pump for 7 days after surgery. Half the cohort had bromodeoxyuridine (BrdU) infused at day 6. Morphometric analysis was conducted of pressure perfusion-fixed grafts harvested at 1 week and 4 weeks. RESULTS: At 1 week, lumen area was similar in both groups (1.82 +/- 0.39 mm(2) placebo vs 1.85 +/- 0.36 mm(2) levcromakalim), although medial cell density and BrdU staining were significantly increased in the placebo group. At 4 weeks, lumen area was unchanged in the placebo group (1.88 +/- 0.51 mm(2)) but had increased to 2.32 +/- 0.46 mm(2) in the levcromakalim group (P = .039 vs 1 week), with a very significant reduction in the intimal area (levcromakalim, 0.06 +/- 0.02 mm(2) vs placebo, 0.33 +/- 0.17 mm(2); P = .001). CONCLUSIONS: Early, short-term treatment with levcromakalim favors expansive remodelling of experimental vein grafts to mimic the effect of external stenting. This expansive remodelling was associated with a reduction in medial cell proliferation at 1 week. CLINICAL RELEVANCE: Critical limb ischemia can be treated by bypass surgery or angioplasty, but inward remodelling with restenosis is a common problem. There has been little previous experimental work to identify treatments associated with expansive remodelling, which would increase the chances of vessel patency. Here, in a randomized trial, we show that short-term treatment with a potassium channel opener (a class of drug that can be used to treat hypertension) results in strong, expansive remodelling, with increases the lumen area and graft size of experimental vein grafts by >25%.